1. Field of the Invention
The present invention relates to new methods of identifying, analyzing, and predicting drug interaction potential, and more specifically the ability of drug metabolites to alter the disposition of other drugs and thereby cause drug interactions.
2. Description of Related Art
Drugs have the potential to be the victim (object) or perpetrator (precipitant) of drug-drug interactions (DDIs), and for this reason, as part of the overall safety evaluation, regulatory agencies like the US Food & Drug Administration (FDA) and European Medicines Agency (EMA) require in vitro testing to ascertain which drug-metabolizing enzymes and drug transporters determine the disposition of a drug (to assess its victim potential) and which drug-metabolizing enzymes and drug transporters are inhibited or induced by a drug (to assess its perpetrator potential). To evaluate a drug's DDI perpetrator potential, the FDA and EMA require that all drugs (drug candidates or investigational drugs) be evaluated for their ability (1) to inhibit seven different cytochrome P450 (CYP) enzymes; (2) to induce three CYP enzymes, and (3) to inhibit 7 drug transporters, as shown in FIG. 1.
The FDA (2012) and EMA (2102) recently issued new guidelines on drug-drug interactions. Whereas previous versions of the guidelines (issued in 2006) focused on the ability of the parent drug to cause DDIs by inhibiting or inducing (i.e., by decreasing or increasing) the metabolism or transport of concomitantly administered drugs, the new guidelines focus on the DDI potential of both the parent drug and significant metabolites present in plasma (i.e., present in the circulation). Regulatory agencies define “significant circulating metabolite” in terms of systemic exposure to the metabolite relative to systemic exposure to the parent drug (both of which are measured as the area under the plasma concentration-time curve or AUC). The FDA defines a “significant circulating metabolite” as any metabolite with a plasma AUC≧25% of parent AUC; the EMA defines it as ≧25% of parent AUC and larger than 10% of the drug-related exposure. The number of significant circulating metabolites can be large. For example, if the parent drug accounts for only 10% of drug-derived material in plasma (based on plasma AUC) then, according the EMA's more restricted definition, there could be as many as nine significant circulating metabolites (each accounting for 10% of drug-related exposure, and each with a plasma AUC greater than 25% of parent drug AUC). There are numerous examples in the literature of drugs that cause clinically significant CYP inhibition due largely or partly to their conversion in vivo to inhibitory metabolites, as summarized in Table 1.
TABLE 1Examples of drugs with circulating metabolites that contribute significantly to CYP inhibition in vivoParent Drug (P)Metabolite (M)[I]Ki[I]KiParent (P)Metabolite (M)CYP(μM)(μM)[I]/Ki(μM)(μM)[I]/KiIPM/IPPAmiodaroneN-2C92.594.60.0261.52.30.6725.3DesethylamiodaroneBupropionThreobupropion2D60.3210.0141.95.40.3624.8Hydroxybupropion2D63.2130.2417.0Erythrobupropion2D60.371.70.2215.3SulfinpyrazoneSulfinpyrazone2C917.82290.0315.0270.196.0sulfideVenlafaxineN-2D60.23300.00780.93200.0476.0DesmethylvenlafaxineAtorvastatinAtorvastatin lactone3A0.06900.00070.0030.90.0045.5AmodiaquineDesethylamodiaquine2D60.082.10.0390.824.10.205.1ClomipramineN-2D60.24160.0140.497.90.0624.2DesmethylclomipramineSertralineN-2D60.086230.00380.14160.0092.4DesmethylsertralineRisperidonePaliperidone3A0.020670.00030.046800.0012.0SertralineN-3A40.333.50.0940.533.50.151.6DesmethylsertralineHaloperidolReduced haloperidol2D60.0230.890.0260.0080.240.0331.3RisperidonePaliperidone2D60.0206.90.00280.046160.0031.0FluoxetineNorfluoxetine2D60.370.22.20.380.22.00.92Taken from a portion of Table 1 in a review article by Yeung et al., 2011, where CYP inhibition (Ki values) by the parent drug (P) and circulating metabolite(s) (M) were determined in vitro with synthetic standards.[I] is the circulating plasma level (in vivo concentration) of inhibitor (parent drug or metabolite);Ki is the inhibition constant determined in vitro;IPM is the in vivo inhibitory potential of the metabolite(s), andIPP is the in vivo inhibitory potential of the parent drug.
Bupropion, for example, has three circulating metabolites that are estimated to inhibit cytochrome P450 2D6 (CYP2D6) in vivo to a much greater extent (>10 fold) than bupropion itself (Table 1). Like the parent drug, significant circulating metabolites meeting the FDA and EMA criteria must be tested in vitro for their ability to function as perpetrators of DDIs (which can amount to a large number of metabolites if the parent drug is extensively metabolized to numerous metabolites). Accordingly, significant circulating metabolites must now be evaluated for their ability to (1) inhibit seven CYP enzymes; (2) induce three CYP enzymes, and (3) inhibit up to nine drug transporters (see FIG. 1). The focus on the DDI perpetrator potential of circulating metabolites in these new regulatory guidelines potentially translates into a considerable burden for pharmaceutical companies, which now face the prospect of having to identify, characterize, and synthesize each significant circulating metabolite and then conduct a large number of in vitro studies.
To comply with these new requirements, pharmaceutical companies can identify and synthesize each significant circulating metabolite and test each synthetic metabolite in vitro for its perpetrator potential, which is expensive and time-consuming, especially where a drug is converted to numerous metabolites. That is, under current methods, the assessment of the contribution of circulating metabolites to CYP inhibition in vivo is currently based on in vitro tests of CYP inhibition by both the parent drug and synthetic standards of its known circulating metabolite(s). This in vitro option was used to generate the data summarized in Table 1. In some cases, however, it is not possible to identify the structure or synthesize the metabolites of a drug (especially if the drug is a natural product with numerous chiral centers); hence, the in vitro approach to evaluating the DDI perpetrator potential of drug metabolites may not even be an option. Researchers can also conduct in vivo studies, which involve administering the drug under investigation together with so-called probe drugs whose disposition in vivo is known to reflect the activity of a particular drug-metabolizing enzyme or drug transporter. Such clinical DDI studies are usually conducted in healthy subjects but in some cases (such as when the drug under investigation is a toxic anti-cancer drug) they are conducted in patients. Such in vivo studies are considered superior to in vitro studies because the study subjects are exposed to the parent drug and its metabolites at pharmacologically relevant concentrations under clinical use conditions. However, to examine a drug's perpetrator potential for all seven of the CYP enzymes and all nine of the drug transporters listed in Table 1 would require a large number of clinical DDI studies, which would be expensive (perhaps prohibitively expensive) and time-consuming. In fact, based on published reports or package inserts (drug labels), no drug has undergone in vivo testing as a clinical inhibitor or inducer of all the CYP enzymes and drug transporters listed in Table 1.
Thus, there remains a need in the art for improved methods of identifying and predicting DDIs, particularly as they are attributable to metabolites of investigational drugs.